The quality of general movements in infants with complex congenital heart disease undergoing surgery in the neonatal period

Background: Advances in diagnostic technologies, surgical management, and perioperative care have increased survival for neonates with complex congenital heart disease (CCHD). The success of these advances exposed a heightened risk of brain injury and developmental disabilities. The General Movements Assessment, a non-invasive method, may detect early neurodevelopmental impairments in high-risk infants. Aims: To examine whether infants with CCHD undergoing neonatal surgery have higher prevalence of atypical general movements (GMs) than a reference group, and whether single ventricle physiology with systemic oxygen saturations <90% increases risk for atypical GMs. Methods: Serial General Movements Assessment (GMA) in a cohort of infants with CCHD (n = 74) at writhing (term-6 weeks) and fidgety (7–17 weeks) GM-age. GMA focused on the presence of definitely abnormal GM-complexity and absent fidgety movements. Single GMAs at 3 months were available from a reference sample of Dutch infants (n = 300). Regression analyses examined relationships between cardiac characteristics and definitely abnormal GM-complexity. Results: Higher prevalence of definitely abnormal GM-complexity in infants with CCHD compared to reference infants (adjusted OR 5.938, 95% CI 2.423–14.355), single ventricle CCHD increased the risk. Occurrence of absent fidgety movements was similar in infants with CCHD and reference infants (adjusted OR 0.475, 95% CI 0.058–3.876). Systemic postoperative oxygen saturations <90% was associated with higher risk of definitely abnormal GM-complexity at fidgety (adjusted OR 16.445 95% CI 1.149–235.281), not at writhing age. Conclusions: Infants with CCHD, especially those with single ventricle CCHD, are at increased risk of definitely abnormal GM-complexity. GMA at fidgety age is recommended

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Neonatal Physical Therapy, Part II: Practice Frameworks and Evidence-Based Practice Guidelines

Purpose: (1) To outline frameworks for neonatal physical therapy based on 3 theoretical models, (2) to describe emerging literature supporting neonatal physical therapy practice, and (3) to identify evidence-based practice recommendations. Key Points: Three models are presented as a framework for neonatal practice: (1) dynamic systems theory including synactive theory and the theory of neuronal group selection, (2) the International Classification of Functioning, Disability and Health, and (3) family-centered care. Literature is summarized to support neonatal physical therapists in the areas of examination, developmental care, intervention, and parent education. Practice recommendations are offered with levels of evidence identified. Conclusions: Neonatal physical therapy practice has a theoretical and evidence-based structure, and evidence is emerging for selected clinical procedures. Continued research to expand the science of neonatal physical therapy is critical to elevate the evidence and support practice recommendations

Neonatal Physical Therapy. Part 1: Clinical Competencies and NICU Clinical Training Models, Part 1

Purpose: To describe clinical training models, delineate clinical competencies, and outline a clinical decision-making algorithm for neonatal physical therapy. Key Points: In these updated practice guidelines, advanced clinical training models, including precepted practicum and residency or fellowship training, are presented to guide practitioners in organizing mentored, competency-based preparation for neonatal care. Clinical competencies in neonatal physical therapy are outlined with advanced clinical proficiencies and knowledge areas specific to each role. An algorithm for decision making on examination, evaluation, intervention, and re-examination processes provides a framework for clinical reasoning. Because of advanced-level competency requirements and the continuous examination, evaluation, and modification of procedures during each patient contact, the intensive care unit is a restricted practice area for physical therapist assistants, physical therapist generalists, and physical therapy students. Conclusions/Practice Implications: Accountable, ethical physical therapy for neonates requires advanced, competency-based training with a preceptor in the pediatric subspecialty of neonatology